Functional Dissection of Pallidal Circuits in Therapeutic Deep Brain Stimulation ABSTRACT Deep brain stimulation (DBS) is a well-established therapy for the motor symptoms of advanced Parkinson's disease (PD) and other neurological disorders. Globus pallidus interna (GPi) and subthalamic nucleus (STN) are widely used DBS targets and have been proven clinically effective in PD therapy. However, it is still unclear which target contributes the better therapeutic effects, and this is compounded by a lack of understanding of the underlying mechanisms. Clinical studies demonstrated no significant differences in motor outcomes of DBS between STN and GPi. However, due to increased reports of cognitive and neuropsychiatric adverse effects and motor symptoms refractory to STN stimulation, interest in GPi DBS is growing. The limited understanding of neural mechanism of action of DBS impedes the further development of GPi DBS as well as rational target selection. The goal of our proposed research is to determine the mechanisms of GPi DBS by monitoring and manipulating activity in relevant neural circuits during quantitative measurement of parkinsonian motor symptoms. The objective of the present work is to establish the therapeutic effects of GPi (entopeduncular nucleus, EP, the homologue of GPi in rats) and to combine optogenetic interventions, multichannel electrophysiology, rodent model of PD, and quantitative behavioral assays to determine the relationship between changes of neural activity in GPi associated neural circuits and changes of motor performance in a skilled forelimb reaching task. We hypothesize that high frequency optogenetic stimulation of GPi local cell bodies will ameliorate PD motor deficits not by increasing or decreasing firing rates, but rather by disrupting pathological oscillatory activity in GPi and associated neural circuits and relieving abnormal neural synchrony within these circuits. Accordingly, using a recently developed ultrafast opsin-Chronos, we will quantify the effects of optogenetic GPi DBS and STN DBS on parkinsonian motor symptoms and quantify the relationship between neural activity in the GPi neural circuit and motor performance during effective (130Hz) and ineffective (20Hz) optogenetic DBS. Elucidating the functional role of the GPi will provide fundamental insights into network dynamics of GPi underlying therapeutic DBS. Ultimately, this project will provide the gateway to understanding the neural substrates of dysfunction in PD and will help with target selection, development and optimization of clinical GPi DBS.